Having studied the statistics of the specific signature residues in the Env protein for SIV infection, and having determined by computation that the founder viruses of the SIV infection differ significantly from the typical virions in the stock inoculum, we examined the changes in the Nef gene and its RNA during the North American HIV epidemic. Using clinical sequence data, Dr Manzourolajdad discovered that the Nef gene had systematically evolved and increased the possibility of alternative folds in Nef RNA. To explore the possibility that Nef perform some of its virological functions through an RNA switching mechanism, we are currently developing general computational tools for identifying alternative folds in riboswitches, to aid in the identification of switches and the corresponding RNA substructures.